A mechanistic understanding of allosteric regulation of neuronal sodium-activated potassium channels

The sodium-activated potassium channel KNa1.1 (KCNT1, Slack, Slo2.2) is found in neurons and couples sodium influx to excitability. Dysfunction of this channel causes intellectual disability and severe epilepsy, for which there is no treatment, making it a potential therapeutic target for a range of neurological conditions. Despite its importance in health and disease, many aspects of its function remain poorly understood. The aim of this project is to develop a molecular understanding of how sodium ions bind to the protein, and how this causes conformational changes, that result in channel opening. Structural approaches involving cryo-EM and molecular dynamics simulations will be used to identify intermediate structural conformations. The structural models developed will be evaluated/refined experimentally by site-directed mutagenesis, electrophysiological measurements, and by identifying state-specific ligands.